Cytochrome P450db; K+ channel

1. The effect of quinidine on the fast-activating, fast-inactivating potassium current (IK(f] in acutely dissociated melanotrophs of the adult rat pituitary was examined. Macroscopic currents were measured by use of the whole-cell configuration of the patch clamp technique. 2. Bath application of quinidine caused a dose-dependent reduction of the peak amplitude of IK(f). The Kd for blockade of IK(f) at 0 mV was estimated to be 41 +/- 5.6 microM. 3. Quinidine elicited a dose-dependent increase of the rate of the decay of IK(f) and this effect was enhanced by membrane depolarization. The possibility that this phenomenon reflects an open channel blocking reaction is discussed. 4. Quinidine also caused a 5 mV hyperpolarizing shift of the steady-state inactivation curve and increased the half-time for recovery from inactivation. Quinidine did not affect the onset of inactivation measured at -30 mV. 5. Internal quinidine did not appear substantially to affect either the peak amplitude or kinetics of IK(f). 6. A study of some structural analogues showed that hydroquinidine and quinacrine had effects similar to those of quinidine. The effect of quinacrine on the amplitude and kinetics of IK(f) was also pH-dependent. Cinchonine, which bears a close structural resemblance to quinidine, was much less effective as a blocker of IK(f).[1]

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Multidrug resistance (MDR) is one of important issues to cause the chemotherapy failure against cancers including gynecological malignancies. Despite some MDR reversal evidences of natural compounds including quinidine and cinchonine, there are no reports on MDR reversal activity of hydrocinchonine with its analogues quinidine and cinchonine especially in uterine sarcoma cells. Thus, in the current study, we comparatively investigated the potent efficacy of hydrocinchonine and its analogues quinidine and cinchonine as MDR-reversal agents for combined therapy with antitumor agent paclitaxel (TAX). Hydrocinchonine, cinchonine, and quinidine significantly increased the cytotoxicity of TAX in P-glycoprotein (gp)-positive MES-SA/DX5, but not in the P-gp-negative MES-SA cells at nontoxic concentrations by 3-(4,5-dimethylthiazol-2-yl)-2,5--diphenyltetrazolium bromide (MTT) assay. Rhodamine assay also revealed that hydrocinchonine, cinchonine, and quinidine effectively enhanced the accumulation of a P-gp substrate, rhodamine in TAX-treated MES-SA/DX5 cells compared with TAX-treated control. In addition, hydrocinchonine, cinchonine, and quinidine effectively cleaved poly (ADP-ribose) polymerase (PARP), activated caspase-3, and downregulated P-gp expression as well as increased sub-G1 apoptotic portion in TAX-treated MES-SA/DX5 cells. Taken together, hydrocinchonine exerted MDR reversal activity and synergistic apoptotic effect with TAX in MES-SA/DX5 cells almost comparable with quinidine and cinchonine as a potent MDR-reversal and combined therapy agent with TAX.[4]

Amphetamine is metabolized by cytochrome P-450 (P450) to p-hydroxyamphetamine and phenylacetone in mammalian species. P450 metabolism is affected by genetic polymorphisms and by xenobiotic interactions in an isozyme-specific fashion. Little is known concerning the isozyme selectivity of amphetamine metabolism. Quinidine selectively inhibits the debrisoquine-specific isozyme (P450db) which displays genetic polymorphism in humans and rats. We now report the effect of quinidine on the metabolism of amphetamine to p-hydroxyamphetamine in vivo. At 0 h male Lewis rats received (po): no treatment (I), 80 mg quinidine/kg in 50% ethanol (II), or 50% ethanol (III), followed at 2 h by 15 mg d-amphetamine sulfate/kg (po). Urine specimens were collected and pooled at 0, 24, and 48 h. Amphetamine and p-hydroxyamphetamine concentrations were determined using a new GC/MS method for simultaneous quantitation. The ethanol vehicle-control (III) had no significant effect on amphetamine metabolism. Quinidine pretreatment (II) resulted in a significant decrease in the excretion of p-hydroxyamphetamine at 24 and 48 h to 7.2 and 24.1% of the vehicle-control levels, respectively, accompanied by a significant increase in amphetamine excretion between 24 and 48 h to 542% of the control. These data show that quinidine inhibits in vivo metabolism of amphetamine in rats and suggest that amphetamine metabolism may, in part, be mediated by an isozyme of P450 which displays genetic polymorphism. The inhibition of amphetamine metabolism results in an increased ratio of parent drug to metabolite concentration (metabolic ratio) in the urine, which mimics the effect of genetic polymorphisms[3].

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This study aimed to investigate the effects of dextromethorphan (DM) or dextromethorphan/quinidine (DM/Q) against pentylenetetrazole (PTZ)- induced seizure threshold in mice and the probable involvement of N-methyl d-aspartate (NMDA), sigma-1 and serotonin 1A (5-HT1A) receptors.
Results: DM (25 and 50 mg/kg) significantly increased PTZ- induced seizure threshold. DM/Q at doses of 10/20 and 25/20 mg/kg had anticonvulsant effect, while at a dose of 50/20 mg/kg attenuated anticonvulsant effect of DM 50 mg/kg. Ketamine (5 mg/kg) or WAY-100635 (1 mg/kg) potentiated, while BD-1047 (2.5 and 5 mg/kg) attenuated the anticonvulsant effect of DM/Q 10/20 mg/kg.
Conclusion: The results of present study demonstrate that combination with quinidine potentiates the anticonvulsant effect of DM at lower doses, while attenuates it at higher dose. Meanwhile, the effects of DM/Q on seizure activity likely involve an interaction with NMDA, the sigma-1 or the 5-HT1A receptor which may be secondary to the elevation of DM levels.[5]

Cytotoxicity assay [4]
Cell Types: MES-SA and MESSA/DX5 Cell
Tested Concentrations: 10 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: demonstrated cytotoxicity to MES-SA cells and can induce cytotoxicity [4]. MES-SA cells in a concentration-dependent manner.

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Apoptosis analysis [4]
Cell Types: MES-SA and MESSA/DX5 Cell
Tested Concentrations: 10 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: The content of sub-G1 DNA in the apoptotic part induced by paclitaxel increased, while paclitaxel did not affect sub-G1 DNA Influence the contents to undergo apoptosis.

Animal/Disease Models: NMRI strain male mice (age 5-6 weeks, weight 25-30 g) [5 doses: 10, 20, 30 mg/kg
Route of Administration: intraperitoneal (ip) injection; 10, 20 and 30 mg/kg;
Experimental Results: vs. The 30 mg/kg dose increased the threshold dose for tonic hindlimb extension attacks compared to the saline-treated control group (p<0.05).

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NMRI male mice (25-30 g) received quinidine (10, 20, and 30 mg/kg), dextromethorphan (DM) (5, 10, 25, and 50 mg/kg) or dextromethorphan/quinidine (DM/Q) (10/20, 25/20, and 50/20 mg/kg), 30 min before the infusion of PTZ. ketamine (1 and 5 mg/kg), BD-1047 (2.5 and 5 mg/kg) or WAY-100635 (0.5 and 1 mg/kg) were administrated as pre-treatment 30 min before the selected dose of DM/Q. Seizures were induced by intravenous PTZ infusion. All data were presented as means ± S.E.M. One-way ANOVA test was used to determine statistical significance (p < 0.05).[5]

Absorption, Distribution and Excretion
The absolute bioavailability of quinidine sulfate is approximately 70%, but it ranges from 45% to 100%. The less-than-complete quinidine sulfate bioavailability is a result of first-pass metabolism in the liver. In contrast, the absolute bioavailability of quinidine gluconate ranges from 70% to 80%, and relative to quinidine sulfate, quinidine from quinidine gluconate has a bioavailability of 1.03. The tmax of quinidine sulfate extended-release tablets is approximately 6 h, while the tmax of quinidine gluconate goes from 3 to 5 h. The peak serum concentration reached with immediate-release quinidine sulfate is delayed for about an hour when taken with food. Furthermore, the ingestion of grapefruit juice may decrease the rate of absorption of quinidine.
The elimination of quinidine is achieved by the renal excretion of the unchanged drug (15 to 40% of total clearance) and its hepatic biotransformation to a variety of metabolites (60 to 85% of total clearance). When urine has a pH lower than 7, 20% of administered quinidine appears in urine unchanged. However, this proportion decreases to as little as 5% as it becomes more alkaline. The renal clearance of quinidine involves both glomerular filtration and active tubular secretion, moderated by pH-dependent tubular reabsorption.
Quinidine has a volume of distribution of 2-3 L/kg in healthy young adults, 0.5 L/kg in patients with congestive heart failure, and 3-5 L/kg in patients with liver cirrhosis.
The clearance of quinidine ranges from 3 to 5 mL/min/kg in adults. In pediatric patients, quinidine clearance may be two or three times as rapid.
The volume of distribution of quinidine is 2 to 3 L/kg in healthy young adults, but this may be reduced to as little as 0.5 L/kg in patients with congestive heart failure, or increased to 3 or 5 L/kg in patients with cirrhosis of the liver. At concentrations of 2 to 5 mg/L (6.5 to 16.2 umol/L), the fraction of quinidine bound to plasma proteins (mainly to (alpha)1-acid glycoprotein and to albumin) is 80 to 88% in adults and older children, but it is lower in pregnant women, and in infants and neonates it may be as low as 50 to 70%. Because (alpha)1-glycoprotein levels are increased in response to stress, serum levels of total quinidine may be greatly increased in settings such as acute myocardial infarction, even though the serum content of unbound (active) drug may remain normal. Protein binding is also increased in chronic renal failure, but binding abruptly descends toward or below normal when heparin is administered for hemodialysis.
...Essentially completely absorbed after oral admin; max effects occur within 1-3 hr, and persist for 6-8 more hr. Large fluctuations in plasma concentration... if repeated doses are given at this interval. ...IM admin... gluconate yields peak effects in 30-90 min.
...All administered compound is excreted by kidney, and about 10-50% appears in urine as unchanged quinidine, within 24 hr.
The bioavailability of quinidine is 70 to 80% after oral use but varies between individuals and preparations. The sulfate salt is rapidly absorbed in 60 to 90 minutes. Polygalacturonate salts produce peak quinidine concentrations in 5 to 6 hours; gastrointestinal absorption of gluconate salts is intermediate (peak 3-4 hours).
For more Absorption, Distribution and Excretion (Complete) data for QUINIDINE (14 total), please visit the HSDB record page.
ABOUT 90% OF QUINIDINE IN PLASMA IS BOUND TO PLASMA PROTEINS (ALPHA/ACID GLYCOPROTEIN AND ALBUMIN) THE DRUG ENTERS ERYTHROCYTES & ... BINDS TO HEMOGLOBIN; AT STEADY STATE, CONCN OF QUINIDINE IN PLASMA & ERYTHROCYTES ARE APPROXIMATELY EQUAL. QUINIDINE ACCUMULATES RAPIDLY IN MOST TISSUES EXCEPT BRAIN, & ... VOL OF DISTRIBUTION IS 2-3 L/KG. /QUINIDINE/
METABOLITES AND SOME OF THE PARENT DRUG (20%) ARE EXCRETED IN URINE; ELIMINATION HALF-TIME IS ABOUT 6 HR. /QUINIDINE/
LIVER METABOLISM & RENAL EXCRETION ARE THE MAIN ROUTES OF ELIMINATION. ENTEROHEPATIC CIRCULATION WOULD NOT SIGNIFICANTLY ALTER ABSORPTION KINETICS AS REFLECTED BY BLOOD CONCENTRATION.
PEAK PLASMA CONCN OF 0.29 UG/ML OF QUINIDINE WERE MEASURED @ 4 HR AFTER ADMIN OF SUSTAINED RELEASE CAPSULE (250 MG QUINIDINE BISULFATE) AND DECLINED STEADILY DURING THE NEXT 8 HR, WHILE AFTER ADMIN OF SUSTAINED RELEASE TABLET (300 MG QUINIDINE SULFATE) THEY WERE FAIRLY EVEN DURING 2-10 HR AFTER DOSING. PLASMA CONCENTRATIONS WERE HIGHER AT LATER TIMES FOR THE CAPSULE THAN FOR THE TABLET. THE BIOAVAILABILITY OF QUINIDINE FROM THE CAPSULES DURING 12 HR WAS 184% COMPARED TO THE TABLET. MEAN QUINIDINE PLASMA CONCN WERE SIGNIFICANTLY GREATER @ 3, 4, 6, 8, & 10 HR AFTER ADMIN OF THE CAPSULE THAN AFTER THE TABLET.
For more Absorption, Distribution and Excretion (Complete) data for QUINIDINE SULFATE (24 total), please visit the HSDB record page.

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Metabolism / Metabolites
Quinidine is mainly metabolized in the liver by cytochrome P450 enzymes, specifically CYP3A4. The major metabolite of quinidine is 3-hydroxy-quinidine, which has a volume of distribution larger than quinidine and an elimination half-life of about 12 hours. Non-clinical and clinical studies suggest that 3-hydroxy-quinidine has approximately half the antiarrhythmic activity of quinidine; therefore, this metabolite is partly responsible for the effects detected with the chronic use of quinidine.
Lactate conjugates of quinidine and its 3-hydroxy metabolite were detected in overdose suicide patient.
Quinidine is metabolized in the liver, principally via hydroxylation to 3-hydroxyquinidine and 2-quinidinone. Some metabolites have antiarrhythmic activity. Approximately 10-50% of a dose is excreted in urine (probably by glomerular filtration) as unchanged drug within 24 hr.
Quinidine metabolites include 3-hydroxyquinidine N-oxide, 2'-oxoquinidinone, desmethylquinidine, and quinidine N-oxide. While metabolism is highly variable between individuals, at least in cases of quinidine-induced torsade de pointes, the metabolites do not appear to contribute to the formation of dysrhythmias.
Quinidine undergoes extensive hepatic oxidative metabolism... One metabolite, 3-hydroxyquinidine, is nearly as potent as quinidine in blocking cardiac sodium channels or prolonging action potentials.
Most quindiidne is eliminated hepatically via the action of cytochrome P450 IIIA.
QUINIDINE YIELDS 2'-HYDROXYQUINIDINE AS METABOLITE IN MAN. /QUINIDINE; FROM TABLE/
MOST URINARY METABOLITES ARE HYDROXYLATED AT ONLY ONE SITE, EITHER ON THE QUINOLINE RING OR ON THE QUINUCLIDINE RING; SMALL AMOUNTS OF DIHYDROXY COMPOUNDS ARE ALSO FOUND. THE FRACTION OF A DOSE OF QUINIDINE THAT IS METABOLIZED & THE METABOLIC PATHWAY APPEAR TO VARY CONSIDERABLY FROM PATIENT TO PATIENT.
Quinidine is metabolized in the liver, principally via hydroxylation to 3-hydroxyquinidine and 2-quinidinone. The metabolites may be pharmacologically active. Approximately 10-50% of a dose is excreted in urine (probably by glomerular filtration) as unchanged drug within 24 hr. /Quinidine/
Quinidine has known human metabolites that include 3-Hydroxyquinidine and Quinidine-N-oxide.

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Biological Half-Life
The elimination half-life of quinidine is 6-8 hours in adults and 3-4 hours in pediatric patients.
Quinidine generally has a plasma half-life of 6-8 hr in healthy inividuals, but half-life may range from 3-16 hr or longer. In one study in patients with Plasmodium falciparum malaria, the elimination half-life of the drug averaged 12.8 hr (range: 6.6-24.8 hr).
The usual plasma half-life of approximately 7 hours after intravenous administration is increased in the presence of chronic liver disease.
THE ELIMINATION HALF-LIFE OF QUINIDINE RANGES FROM 4 TO 10 HR IN HEALTHY PERSONS, WITH USUAL MEAN VALUE OF 6 TO 7 HR. HALF-LIFE IS SIGNIFICANTLY PROLONGED IN ELDERLY PERSONS, EVEN WHEN THEY ARE APPARENTLY HEALTHY. /QUINIDINE/
... EXCRETED IN URINE; ELIMINATION HALF-TIME IS ABOUT 6 HR. /QUINIDINE/
Quinidine generally has a plasma half-life of 6-8 hr in healthy individuals, but half-life may range from 3-16 hr or longer. In one study in patients with Plasmodium falciparum malaria, the elimination half-life of the drug averaged 12.8 hr (range: 6.6-24.8 hr). /Quinidine/

Toxicity Summary
IDENTIFICATION: Quinidine is a class lA antiarrhythmic drug. Origin of the substance: Quinidine is the d- isomer of quinine. Quinidine is an alkaloid that may be derived from various species of Cinchona. Cinchona barks contain 0.25 to 3.0% quinidine. Quinidine is also prepared from quinine. Quinidine is a powder or white crystals, odorless with a bitter taste. Quinidine bisulfate is colorless crystals which is odorless and has a bitter taste. Quinidine gluconate is a white powder which is odorless and has a bitter taste. Quinidine poly-galacturonate is a powder. Quinidine sulfate is a white powder or odorless crystals with a bitter taste. Indications: Description: Premature ventricular extrasystoles and ventricular tachycardia; supraventricular arrhythmia; maintenance of sinus rhythm after cardioversion of atrial flutter or fibrillation. HUMAN EXPOSURE: Main risks and target organs: Cardio-toxicity is the main risk of quinidine poisoning. Quinidine may induce central nervous system symptoms. Summary of clinical effects: Toxic effects appear within 2 - 4 hours after ingestion but the delay may vary according to the quinidine salt and to the preparation forms. Symptoms may include disturbances of cardiac rhythm (especially in patients with underlying cardiovascular disease), neurotoxicity and respiratory depression. Diagnosis: Cardiac disturbances: circulatory arrest, shock, conduction disturbances, ventricular arrhythmias, ECG changes, Neurological symptoms: tinnitus, drowsiness, syncope, coma, convulsions, delirium. Respiratory depression. Quinidine concentrations may be helpful in diagnosis but are not useful for clinical management. Contraindications: Allergy or idiosyncrasy to cinchona alkaloids; atrioventricular or complete heart block; intraventricular conduction defects; absence of atrial activity; digitalis intoxication; myasthenia gravis and ventricular dysrhythmia of the torsades de pointes type Precautions include the following: Congestive heart failure, hypotension, renal disease, hepatic failure; concurrent use of other antiarrhythmic drugs; old age and breast-feeding. Routes of entry: Oral: Oral absorption is the most frequent cause of intoxication. Parenteral: Intoxication after IV administration is rare but has been reported in patients treated with IV quinidine for cardiac dysrhythmia. Absorption by route of exposure: Oral: Quinidine is almost completely absorbed from the gastrointestinal tract. However, because of hepatic first-pass effect, the absolute bioavailability is about 70 to 80% of the ingested dose and may vary between patients and preparations. The time to plasma peak concentration is 1 to 3 hours for quinidine sulfate, 3 to 6 hours for quinidine gluconate and about 6 hours for quinidine polygalacturonate. Sustained-release quinidine is absorbed continuously over 8 to 12 hours. Parenteral: Absorption of quinidine after intramuscular injection may be erratic and unpredictable with incomplete absorption of the administered dose, probably due to precipitation of drug at the site of injection. Other studies indicate no difference between the rate of quinidine absorption when given by intramuscular injection or oral absorption. Distribution by route of exposure: Oral: Protein binding: About 70 to 80% of the drug is bound to plasma protein. Plasma protein binding is decreased in patients with chronic liver disease. Tissue: Quinidine concentrations in liver are 10 to 30 times higher than those in plasma. Skeletal and cardiac muscle, brain and other tissues contain intermediate amounts. The red cell plasma partition ratio is 0.82. Biological half-life by route of exposure: Elimination half-life: The half-life is about 6 to 7 hours. It is increased in chronic liver disease and in the elderly. It does not appear to be altered in congestive heart failure or renal failure. Metabolism: 50 to 90% of quinidine is metabolized in the liver to hydroxylated products. Metabolites include 3-hydroxyquinidine, 2 oxoquinidinone, 0-desmethylquinidine, quinidine-N-oxide. The principal metabolite is 3 hydroxyquinidine which exerts similar effects to quinidine and may account for part of the observed antiarrhythmic effects. The elimination kinetics of hydroxyquinidine appear to be similar to those of quinidine. Elimination by route of exposure Kidney: The amount excreted unchanged in urine is variable but is about 17% of an administered dose. Up to 50% of a dose of quinidine (unchanged + metabolites) is excreted in urine within 24 hours after administration. Renal excretion is dependent upon the pH of the urine. Excretion varies inversely with urine pH. Excretion is reduced in renal insufficiency and in congestive heart failure. Liver: 50 to 90% of a dose of quinidine is metabolized in the liver. Bile: Approximately 1 to 3% is excreted in the feces via the bile. Breast milk: Quinidine is excreted in breast milk. Mode of action Toxicodynamics: Quinidine reduces the permeability of heart muscle to electrolytes (membrane stabilizer) and is a general cardiac depressant. It has a negative inotropic effect; inhibits the spontaneous diastolic depolarization; slow conduction; lengthens the effective refractory period; and raises the electrical threshold. This results in depression of contractility, impaired conductivity (atrioventricular and intraventricular) and decreased excitability but with possible abnormal stimulus re-entry mechanism. Quinidine has an anticholinergic effect and peripheral vasodilator properties. In experimental studies the following progression changes was observed: ECG: bradycardia, prolongation of the PR interval, lengthening of the QT interval, widening of the QRS with development of an idioventricular rhythm and then in ventricular standstill. Sometimes the terminal event was ventricular fibrillation. Blood pressure decreases progressively. A significant decrease of blood pressure was noted with the appearance of QRS widening and blood pressure was close to zero when slow idioventricular rhythm appeared. Electrolytes abnormalities: decrease in plasma concentrations of potassium, sodium and magnesium with the development of acidosis. Electrolytes: Hypokalaemia may occur and is probably related to an intracellular transport of potassium by a direct effect on cellular membrane permeability. Neurologic symptoms: Syncope and convulsions may represent a direct toxic effect on CNS or may be related to cerebral ischaemia due to circulatory or respiratory failure. Pharmacodynamics: Quinidine slows the rate of firing of the normal and of ectopic rhythmic foci; it raises the threshold for electrically induced arrhythmias; it protects against ventricular arrhythmias; and it prevents or terminates circus movement flutter. Teratogenicity: Quinidine has been implicated as a cause of light cranial nerve damage to the fetus at doses much larger than those needed to treat arrhythmias. Interactions: Several interactions have been reported. Quinidine has a synergistic action with warfarin (decrease of prothrombin level). Quinidine potentiates both non-depolarizing and depolarizing neuromuscular blocking agents. The cardiodepressant effects of other antiarrhythmic agents are increased by concurrent use of quinidine; amiodarone increases quinidine concentrations in the blood. Quinidine concentrations are reduced by: rifampicin, anticonvulsants, nifedipine and acetazolamide. Quinidine concentrations are increased by antacids, cimetidine, verapamil and amiodarone; the risk of quinidine toxicity is increased by terfenadine, astemizole, and thiazide and loop diuretics. Quinidine increases the plasma concentrations of propafenone and digoxin. Main adverse effects: Numerous adverse effects during quinidine therapy have been reported. Cardiovascular: Hypotension after IV administration; Syncope; proarrhythmic effect: "torsades de pointes"; and ECG: widening of QRS interval; prolongation of PR and QT intervals. CNS: Cinchonism: headache, fever, visual disturbances, mydriasis, tinnitus, nausea, vomiting and rashes. Gastrointestinal: Nausea, vomiting, diarrhoea, colic have been reported. Hepatic: Granulomatous hepatitis or hepatitis with centrilobular necrosis. Skin: Skin rashes with drug fever and photosensitivity may result. Hematologic: Thrombocytopenia (immunologic reaction) has been noted. Clinical effects: Acute poisoning: Ingestion: Severity of quinidine poisoning is related to the cardiotoxic effects. Symptoms appear usually within 2 to 4 hours and may include: cardiovascular symptoms: hypotension, cardiogenic shock, cardiac arrest. ECG may show: decrease of T wave; prolongation of QT and QRS intervals; atrioventricular block; ventricular dysrhythmia (torsade de pointes). Neurological symptoms: tinnitus, drowsiness, syncope, coma, convulsion, blurred vision and diplopia. Respiratory symptoms: hypoventilation and apnea. Cardiotoxicity may be enhanced if other cardiotoxic drugs have been ingested (antiarrhythmic drugs, tricyclic antidepressants). Parenteral exposure: After IV administration symptoms appear more rapidly. Chronic poisoning: Ingestion: The most relevant symptoms of chronic poisoning are: ECG disturbances; syncope due to ventricular dysrhythmia, (torsade de pointes) and cinchonism gastrointestinal disturbances Course, prognosis, cause of death: The usual course of quinidine poisoning is dominated by the cardiovascular disturbances which usually occur within 2 to 4 first hours but may first appear as late as 12 hours after exposure (and perhaps even later after ingestion of a slow- release preparation). Symptoms may last for 24 to 36 hours. Patients who survive 48 hours after acute poisoning are likely to recover. Death may result from cardiac arrest by asystole or electromechanical dissociation and, rarely, by ventricular fibrillation. Systematic description of clinical effects: Cardiovascular: Acute: Cardiovascular symptoms are the major features of quinidine toxicity. Tachycardia due to anticholinergic effects is usually observed initially or in moderate intoxication. In severe intoxication, bradycardia due to atrioventricular block may occur. Hypotension and shock: hypotension due to peripheral vasodilation is common. In severe intoxication, cardiogenic shock with increased central venous pressure is usually observed and is related to decreased cardiac contractility. Cardiac arrest may occur, which may be related to electromechanical dissociation, ventricular dysrhythmia or asystole. Cardiac dysrhythmias are common and may include: atrioventricular block, idioventricular rhythm, ventricular tachycardia and fibrillation, torsades de pointes. ECG changes are always present in symptomatic intoxication: repolarization abnormalities, decreased T wave, increase of U wave, prolongation of QT and PR intervals, widening of QRS complexes (> 0.08 sec), atrioventricular block. Syncope due to torsade de pointes may occur. Chronic: ECG changes with repolarization abnormalities, decreased T wave and increase of QT interval are a common feature during quinidine therapy. Syncope is related to transient torsade de pointes and occurs in 1 to 8% of patients receiving quinidine. The occurrence of torsade de pointes is not correlated with plasma quinidine levels but is favored by an increase in the QT interval. Respiratory: Acute: Respiratory depression or apnea is mostly associated with severe cardiac disturbances such as shock or ventricular dysrhythmia. Pulmonary edema with normal pulmonary capillary wedge pressure following an attempted suicide has been documented. Neurological: CNS: Acute: Drowsiness, delirium, coma and convulsions may appear without cardiac symptoms. However, cardiac failure should always be considered when CNS symptoms appear. Cinchonism may sometimes appear. Chronic: Cinchonism. Delirium has been reported. Peripheral nervous system: Chronic: Quinidine can potentiate the neuromuscular blocking action of some skeletal muscle relaxants and may cause the return of respiratory paralysis if it is given shortly after recovery from neuromuscular blockade. Autonomic nervous system: Acute: Quinidine has an anticholinergic effect. However, this effect is usually limited to the vagal system. Skeletal and smooth muscle: Chronic: An increase in serum concentrations of skeletal muscle enzymes has been reported in a man treated with quinidine. Gastrointestinal: Acute: Nausea and vomiting may occur. Chronic: Gastrointestinal toxicity (nausea, vomiting, diarrhea and colic) is the most frequent side effect of quinidine. Hepatic: Chronic: Hepatotoxicity has been reported, with an increase in serum concentrations of transaminases, LDH, alkaline phosphatase, and cholestasis. Renal: Acute: No direct nephrotoxic effect has been reported. Acute renal failure related to cardiogenic shock may occur. Dermatological: Chronic: Skin lesions have been attributed to the use of quinidine and include skin rash, photosensitivity and lichen planus. Eye, ear, nose, throat: local effects: Acute: Cinchonism is rarely observed in acute poisonings. Toxic amblyopia, scotoma and impaired color perception may occur at toxic doses. Chronic: Chronic cumulative overdose may cause cinchonism: headache, tinnitus, vertigo, mydriasis, blurred vision, diplopia, photophobia, deafness, and corneal deposits have been reported in a patient who took quinidine for two years. Hematological: Chronic: Thrombocytopenia and hemolytic anemia of immunologic origins have been reported. Immunological: Chronic: Quinidine may cause several immunologic mediated reactions: thrombocytopenia, hemolytic anemia, angioneurotic edema, skin rash, fever. Metabolic: Acid-base disturbances: Acute: Metabolic acidosis may occur in severe intoxication with shock. Fluid and electrolyte disturbances: Acute: Hypokalemia is frequently observed. Special risks: Pregnancy: Chronic: Quinidine has been implicated as a cause of cranial nerve damage to the fetus at doses much larger than those needed to treat arrhythmia. In a neonate born to a woman taking quinidine throughout pregnancy, serum levels were equal to that of the mother. The child's ECG was normal and there was no evidence of teratogenicity. Breast-feeding: Chronic: Quinidine is present in breast milk at levels slightly lower than serum levels. The dose of quinidine received by an infant taking 1l of milk would be below therapeutic doses. However, breast-feeding is not recommended because of potential quinidine accumulation in the immature newborn liver.
IDENTIFICATION: Quinidine is a class lA antiarrhythmic drug. Origin of the substance: Quinidine is the d- isomer of quinine. Quinidine is an alkaloid that may be derived from various species of Cinchona. Cinchona barks contain 0.25 to 3.0% quinidine. Quinidine is also prepared from quinine. Quinidine is a powder or white crystals, odorless with a bitter taste. Quinidine bisulfate is colorless crystals which is odorless and has a bitter taste. Quinidine gluconate is a white powder which is odorless and has a bitter taste. Quinidine poly-galacturonate is a powder. Quinidine sulfate is a white powder or odorless crystals with a bitter taste. Indications: Description: Premature ventricular extrasystoles and ventricular tachycardia; supraventricular arrhythmia; maintenance of sinus rhythm after cardioversion of atrial flutter or fibrillation. HUMAN EXPOSURE: Main risks and target organs: Cardio-toxicity is the main risk of quinidine poisoning. Quinidine may induce central nervous system symptoms. Summary of clinical effects: Toxic effects appear within 2 - 4 hours after ingestion but the delay may vary according to the quinidine salt and to the preparation forms. Symptoms may include disturbances of cardiac rhythm (especially in patients with underlying cardiovascular disease), neurotoxicity and respiratory depression. Diagnosis: Cardiac disturbances: circulatory arrest, shock, conduction disturbances, ventricular arrhythmias, ECG changes, Neurological symptoms: tinnitus, drowsiness, syncope, coma, convulsions, delirium. Respiratory depression. Quinidine concentrations may be helpful in diagnosis but are not useful for clinical management. Contraindications: Allergy or idiosyncrasy to cinchona alkaloids; atrioventricular or complete heart block; intraventricular conduction defects; absence of atrial activity; digitalis intoxication; myasthenia gravis and ventricular dysrhythmia of the torsades de pointes type Precautions include the following: Congestive heart failure, hypotension, renal disease, hepatic failure; concurrent use of other antiarhythmic drugs; old age and breast-feeding. Routes of entry: Oral: Oral absorption is the most frequent cause of intoxication. Parenteral: Intoxication after IV administration is rare but has been reported in patients treated with IV quinidine for cardiac dysrhythmia. Absorption by route of exposure: Oral: Quinidine is almost completely absorbed from the gastrointestinal tract. However, because of hepatic first-pass effect, the absolute bioavailability is about 70 to 80% of the ingested dose and may vary between patients and preparations. The time to plasma peak concentration is 1 to 3 hours for quinidine sulfate, 3 to 6 hours for quinidine gluconate and about 6 hours for quinidine polygalacturonate. Sustained-release quinidine is absorbed continuously over 8 to 12 hours. Parenteral: Absorption of quinidine after intramuscular injection may be erratic and unpredictable with incomplete absorption of the administered dose, probably due to precipitation of drug at the site of injection. Other studies indicate no difference between the rate of quinidine absorption when given by intramuscular injection or oral absorption. Distribution by route of exposure: Oral: Protein binding: About 70 to 80% of the drug is bound to plasma protein. Plasma protein binding is decreased in patients with chronic liver disease. Tissue: Quinidine concentrations in liver are 10 to 30 times higher than those in plasma. Skeletal and cardiac muscle, brain and other tissues contain intermediate amounts. The red cell plasma partition ratio is 0.82. Biological half-life by route of exposure: Elimination half-life: The half-life is about 6 to 7 hours. It is increased in chronic liver disease and in the elderly. It does not appear to be altered in congestive heart failure or renal failure. Metabolism: 50 to 90% of quinidine is metabolized in the liver to hydroxylated products. Metabolites include 3-hydroxyquinidine, 2 oxoquinidinone, 0-desmethylquinidine, quinidine-N-oxide. The principal metabolite is 3 hydroxyquinidine which exerts similar effects to quinidine and may account for part of the observed antiarrhythmic effects. The elimination kinetics of hydroxyquinidine appear to be similar to those of quinidine. Elimination by route of exposure Kidney: The amount excreted unchanged in urine is variable but is about 17% of an administered dose. Up to 50% of a dose of quinidine (unchanged + metabolites) is excreted in urine within 24 hours after administration. Renal excretion is dependent upon the pH of the urine. Excretion varies inversely with urine pH. Excretion is reduced in renal insufficiency and in congestive heart failure. Liver: 50 to 90% of a dose of quinidine is metabolized in the liver. Bile: Approximately 1 to 3% is excreted in the feces via the bile. Breast milk: Quinidine is excreted in breast milk. Mode of action Toxicodynamics: Quinidine reduces the permeability of heart muscle to electrolytes (membrane stabilizer) and is a general cardiac depressant. It has a negative inotropic effect; inhibits the spontaneous diastolic depolarization; slow conduction; lengthens the effective refractory period; and raises the electrical threshold. This results in depression of contractility, impaired conductivity (atrioventricular and intraventricular) and decreased excitability but with possible abnormal stimulus re-entry mechanism. Quinidine has an anticholinergic effect and peripheral vasodilator properties. In experimental studies the following progression changes was observed: ECG: bradycardia, prolongation of the PR interval, lengthening of the QT interval, widening of the QRS with development of an idioventricular rhythm and then in ventricular standstill. Sometimes the terminal event was ventricular fibrillation. Blood pressure decreases progressively. A significant decrease of blood pressure was noted with the appearance of QRS widening and blood pressure was close to zero when slow idioventricular rhythm appeared. Electrolytes abnormalities: decrease in plasma concentrations of potassium, sodium and magnesium with the development of acidosis. Electrolytes: Hypokalaemia may occur and is probably related to an intracellular transport of potassium by a direct effect on cellular membrane permeability. Neurologic symptoms: Syncope and convulsions may represent a direct toxic effect on CNS or may be related to cerebral ischaemia due to circulatory or respiratory failure. Pharmacodynamics: Quinidine slows the rate of firing of the normal and of ectopic rhythmic foci; it raises the threshold for electrically induced arrhythmias; it protects against ventricular arrhythmias; and it prevents or terminates circus movement flutter. Teratogenicity: Quinidine has been implicated as a cause of light cranial nerve damage to the fetus at doses much larger than those needed to treat arrhythmias. Interactions: Several interactions have been reported. Quinidine has a synergistic action with warfarin (decrease of prothrombin level). Quinidine potentiates both non-depolarizing and depolarizing neuromuscular blocking agents. The cardiodepressant effects of other antiarrhythmic agents are increased by concurrent use of quinidine; amiodarone increases quinidine concentrations in the blood. Quinidine concentrations are reduced by: rifampicin, anticonvulsants, nifedipine and acetazolamide. Quinidine concentrations are increased by antacids, cimetidine, verapamil and amiodarone; the risk of quinidine toxicity is increased by terfenadine, astemizole, and thiazide and loop diuretics. Quinidine increases the plasma concentrations of propafenone and digoxin. Main adverse effects: Numerous adverse effects during quinidine therapy have been reported. Cardiovascular: Hypotension after IV administration; Syncope; proarrhythmic effect: "torsades de pointes"; and ECG: widening of QRS interval; prolongation of PR and QT intervals. CNS: Cinchonism: headache, fever, visual disturbances, mydriasis, tinnitus, nausea, vomiting and rashes. Gastrointestinal: Nausea, vomiting, diarrhoea, colic have been reported. Hepatic: Granulomatous hepatitis or hepatitis with centrilobular necrosis. Skin: Skin rashes with drug fever and photosensitivity may result. Hematologic: Thrombocytopenia (immunologic reaction) has been noted. Clinical effects: Acute poisoning: Ingestion: Severity of quinidine poisoning is related to the cardiotoxic effects. Symptoms appear usually within 2 to 4 hours and may include: cardiovascular symptoms: hypotension, cardiogenic shock, cardiac arrest. ECG may show: decrease of T wave; prolongation of QT and QRS intervals; atrioventricular block; ventricular dysrhythmia (torsade de pointes). Neurological symptoms: tinnitus, drowsiness, syncope, coma, convulsion, blurred vision and diplopia. Respiratory symptoms: hypoventilation and apnea. Cardiotoxicity may be enhanced if other cardiotoxic drugs have been ingested (antiarrhythmic drugs, tricyclic antidepressants). Parenteral exposure: After IV administration symptoms appear more rapidly. Chronic poisoning: Ingestion: The most relevant symptoms of chronic poisoning are: ECG disturbances; syncope due to ventricular dysrhythmia, (torsade de pointes) and cinchonism gastrointestinal disturbances Course, prognosis, cause of death: The usual course of quinidine poisoning is dominated by the cardiovascular disturbances which usually occur within 2 to 4 first hours but may first appear as late as 12 hours after exposure (and perhaps even later after ingestion of a slow- release preparation). Symptoms may last for 24 to 36 hours. Patients who survive 48 hours after acute poisoning are likely to recover. Death may result from cardiac arrest by asystole or electromechanical dissociation and, rarely, by ventricular fibrillation. Systematic description of clinical effects: Cardiovascular: Acute: Cardiovascular symptoms are the major features of quinidine toxicity. Tachycardia due to anticholinergic effects is usually observed initially or in moderate intoxication. In severe intoxication, bradycardia due to atrioventricular block may occur. Hypotension and shock: hypotension due to peripheral vasodilation is common. In severe intoxication, cardiogenic shock with increased central venous pressure is usually observed and is related to decreased cardiac contractility. Cardiac arrest may occur, which may be related to electromechanical dissociation, ventricular dysrhythmia or asystole. Cardiac dysrhythmias are common and may include: atrioventricular block, idioventricular rhythm, ventricular tachycardia and fibrillation, torsades de pointes. ECG changes are always present in symptomatic intoxication: repolarization abnormalities, decreased T wave, increase of U wave, prolongation of QT and PR intervals, widening of QRS complexes (> 0.08 sec), atrioventricular block. Syncope due to torsade de pointes may occur. Chronic: ECG changes with repolarization abnormalities, decreased T wave and increase of QT interval are a common feature during quinidine therapy. Syncope is related to transient torsade de pointes and occurs in 1 to 8% of patients receiving quinidine. The occurrence of torsade de pointes is not correlated with plasma quinidine levels but is favored by an increase in the QT interval. Respiratory: Acute: Respiratory depression or apnea is mostly associated with severe cardiac disturbances such as shock or ventricular dysrhythmia. Pulmonary edema with normal pulmonary capillary wedge pressure following an attempted suicide has been documented. Neurological: CNS: Acute: Drowsiness, delirium, coma and convulsions may appear without cardiac symptoms. However, cardiac failure should always be considered when CNS symptoms appear. Cinchonism may sometimes appear. Chronic: Cinchonism. Delirium has been reported. Peripheral nervous system: Chronic: Quinidine can potentiate the neuromuscular blocking action of some skeletal muscle relaxants and may cause the return of respiratory paralysis if it is given shortly after recovery from neuromuscular blockade. Autonomic nervous system: Acute: Quinidine has an anticholinergic effect. However, this effect is usually limited to the vagal system. Skeletal and smooth muscle: Chronic: An increase in serum concentrations of skeletal muscle enzymes has been reported in a man treated with quinidine. Gastrointestinal: Acute: Nausea and vomiting may occur. Chronic: Gastrointestinal toxicity (nausea, vomiting, diarrhea and colic) is the most frequent side effect of quinidine. Hepatic: Chronic: Hepatotoxicity has been reported, with an increase in serum concentrations of transaminases, LDH, alkaline phosphatase, and cholestasis. Renal: Acute: No direct nephrotoxic effect has been reported. Acute renal failure related to cardiogenic shock may occur. Dermatological: Chronic: Skin lesions have been attributed to the use of quinidine and include skin rash, photosensitivity and lichen planus. Eye, ear, nose, throat: local effects: Acute: Cinchonism is rarely observed in acute poisonings. Toxic amblyopia, scotoma and impaired color perception may occur at toxic doses. Chronic: Chronic cumulative overdose may cause cinchonism: headache, tinnitus, vertigo, mydriasis, blurred vision, diplopia, photophobia, deafness, and corneal deposits have been reported in a patient who took quinidine for two years. Hematological: Chronic: Thrombocytopenia and hemolytic anemia of immunologic origins have been reported. Immunological: Chronic: Quinidine may cause several immunologic mediated reactions: thrombocytopenia, hemolytic anemia, angioneurotic edema, skin rash, fever. Metabolic: Acid-base disturbances: Acute: Metabolic acidosis may occur in severe intoxication with shock. Fluid and electrolyte disturbances: Acute: Hypokalemia is frequently observed. Special risks: Pregnancy: Chronic: Quinidine has been implicated as a cause of cranial nerve damage to the fetus at doses much larger than those needed to treat arrhythmia. In a neonate born to a woman taking quinidine throughout pregnancy, serum levels were equal to that of the mother. The child's ECG was normal and there was no evidence of teratogenicity. Breast-feeding: Chronic: Quinidine is present in breast milk at levels slightly lower than serum levels. The dose of quinidine received by an infant taking 1l of milk would be below therapeutic doses. However, breast-feeding is not recommended because of potential quinidine accumulation in the immature newborn liver. /Quinidine/

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Hepatotoxicity
Chronic therapy with quinidine is associated with a low rate of serum enzyme elevations, which are usually mild, asymptomatic and self limited even without alteration in dose. In addition, there have been many reports of acute hypersensitivity reactions to quinidine that include hepatic involvement. The reactions usually arise after 1 to 2 weeks of therapy, but can appear within 24 hours of restarting quinidine or with rechallenge. The clinical features are marked by fatigue, nausea, vomiting, diffuse muscle aches, arthralgias and high fever. Blood testing at an early stage shows increases in serum aminotransferase and alkaline phosphatase levels as well as mild jaundice, which can deepen for a few days even after stopping quinidine. The pattern of serum enzymes elevations is typically cholestatic or mixed. Rash is uncommon and eosinophilia is not typical, despite the presence of other signs of hypersensitivity (fever, arthralgias). Autoantibodies are not typically found. Liver biopsies usually show mild injury and small epithelioid granulomas, as are often found in many organs during systemic hypersensitivity reactions. A similar clinical signature of liver injury occurs with quinine, an optical isomer of quinidine that is used predominantly as an antimalarial agent. In recent years, there have been few reports of liver injury attributed to quinidine, probably because it is now rarely used.
Likelihood score: A (well established cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal doses of quinidine up to 1.8 grams daily produce low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Exclusively breastfed infants should be carefully monitored if this drug is used during lactation, possibly including measurement of serum levels to rule out toxicity if there is a concern.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
From 6.5 to 16.2 µmol/L, 80 to 88% of quinidine is bound to plasma proteins, mainly α1-acid glycoprotein and albumin. This fraction is lower in pregnant women, and it may be as low as 50 to 70% in infants and neonates.

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Interactions
The combination of propranolol and quinidine resulted in increased beta-blockade measured by reduction in exercise heart rate and prolongation of the QTc and PR intervals ... quinidine stereoselectively inhibits the metabolism of propranolol through inhibition of the debrisoquin isozyme. The increased concentration of propranolol produced by quinidine results in increased beta-blockade.
Ethacrynic acid and furosemide /diuretics/ increase lipid solubility and tubular reabsorption of quinidine and thus prolong its therapeutic effects/ ...but will not alkalinize urine... .
Quinidine may potentiate the effects of both nondepolarizing and depolarizing skeletal muscle relaxants such as pancuronium bromide, succinylcholine chloride, and tubocurarine chloride. Neostigmine methylsulfate does not appear to reverse these effects.
Quinidine shoul

[1]. Quinidine. [Updated 2023 Aug 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

Therapeutic Uses
Adrenergic alpha-Antagonists; Anti-Arrhythmia Agents; Antimalarials; Enzyme Inhibitors; Muscarinic Antagonists
Quinidine is indicated in the treatment of recurrent, documented, life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. Quinidine should not be used to treat ventricular arrhythmias of lesser severity, such as asymptomatic ventricular premature contractions. /Included in US product labeling/
Quinidine is indicated in the treatment of symptomatic atrial fibrillation or flutter in patients whose symptoms are not controlled by measures to reduce the rate of ventricular response. /US Product Labeling/
Chronic quinidine treatment is indicated for some patients at high risk for symptomatic atrial fibrillation pr flutter, such as those who have had previous episodes taht are so frequent and poorly tolerated as to outweigh the risk of porphylactic therapy with quinidine. /US Product Labeling/
Intravenous quinidine is indicated in the treatment of life-threatening Plasmodium falciparum malaria. /US Product Labeling/
MEDICATION (VET): OF 6 ANTIARRHYTHMICS TESTED, QUINIDINE BISULFATE GAVE NO PROTECTION AGAINST THE INDUCED ARRHYTHMIA IN DOGS.
... IS EFFECTIVE FOR SHORT- AND LONG-TERM TREATMENT OF SUPRAVENTRICULAR AND VENTRICULAR ARRHYTHMIAS. /QUINIDINE/
FOR PRACTICAL PURPOSES, QUINIDINE IS ONLY GIVEN ORALLY, ALTHOUGH IT CAN BE ADMINEITHER IM OR IV UNDER SPECIAL CIRCUMSTANCES. THE USUAL ORAL DOSE OF QUINIDINE SULFATE IS 200 TO 300 MG THREE TO FOUR TIMES A DAY. ... FOR PATIENTS WITH PREMATURE ATRIAL OR VENTRICULAR CONTRACTIONS OR MAINTENANCE THERAPY. HIGHER AND/OR MORE FREQUENT DOSES CAN BE USED FOR LIMITED PERIODS FOR TREATMENT OF PAROXYSMAL VENTRICULAR TACHYCARDIA.
Quinidine is used primarily as prophylactic therapy to maintain normal sinus rhythm after conversion of atrial fibrillation and/or flutter by other methods. The drug is also used to prevent the recurrence of paroxysmal atrial fibrillation, paroxysmal atrial tachycardia, paroxysmal atrioventricular junctional rhythm, paroxysmal ventricular tachycardia, and atrial or ventricular premature contractions.
For more Therapeutic Uses (Complete) data for QUINIDINE SULFATE (7 total), please visit the HSDB record page.

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Drug Warnings
Skin reactions to quinidine are rare and include morbilliform and scarlatiniformeruptions, urticaria, rash, pruritus, exfoliative dermatitis, eczema, severe exacerbation of psoriasis, lichenoid reactions, flushing, pigmentary abnormalities, photodermatitis (photosensitivity), and contact dermatitis.
... Adverse reactions are not related to plasma concentration and include drug fever cholestatic hepatitis, systemic lupus erythematosus, asthma, anaphylaxis, thrombocytopenia, hemolytic anemia (especially in glutcose-6-phosphate dehydrogenase deficiency), and hypoprothrombinemia. Skin changes range from maculopapular eruption to thrombocytopenic purpura, cutaneous vasculitis, photosensitivity, and bullous lesions.
Drug induced agranulocytosisis a clinical entity characterized by a selective reduction of circulating neutrophils, usually to a level less than 0.2X10+9/l in relation to the administration of the drug. Quinidine is an antiarrhythmic agent widely used on an outpatient basis with some well known hematological side effects. Its midterm administration has been related to a few cases of agranulocytosis. The case of a 60 yr old man with atrial fibrillation is described who presented quinidine induced agranulocytosis of abrupt onset only 3 days after the exposure to the drug, recovering normal levels of neutrophils during the third hospitalization day.
Large doses ...increase temporal dispersion of ventricular refractory periods ...may induce idioventricular impulse generation. Caution ...mandatory in ...treatment of ventricular ectopic rhythms; increased dose after therapeutic failure may increase hazard.
For more Drug Warnings (Complete) data for QUINIDINE (34 total), please visit the HSDB record page.
OCCASIONALLY PATIENTS TAKING QUINIDINE EXPERIENCE SYNCOPE OR SUDDEN DEATH. ... MAY BE RESULT OF HIGH CONCENTRATIONS OF QUINIDINE IN PLASMA OR RESULT OF COEXISTING DIGITALIS TOXICITY. /QUINIDINE/
INDIVIDUALS WITH THE LONG Q-T SYNDROME OR THOSE WHO RESPOND TO LOW CONCENTRATIONS OF QUINIDINE WITH MARKED LENGTHENING OF THE Q-T INTERVAL APPEAR TO BE PARTICULARLY AT RISK /OF SYNCOPE OR SUDDEN DEATH/ AND SHOULD NOT BE TREATED WITH THIS DRUG. /QUINIDINE/
EXCESSIVE CONCENTRATION OF DRUG IN PLASMA WILL CAUSE ADVERSE EFFECTS IN ANY PATIENT. BECAUSE QUINIDINE HAS LOW THERAPEUTIC RATIO, CONSTANT VIGILANCE IS THUS REQUIRED IN EVERY PATIENT TAKING THIS DRUG. /QUINIDINE/
Quinidine should be used with extreme caution, if at all, in patients with incomplete atrioventricular nodal block, since complete heart block and asystole may result. Im or iv administration of quinidine is especially hazardous in the presence of atrioventricular block, in the absence of atrial activity, and the patients with extensive myocardial injury. Hypokalemia, hypoxia, and disorders of acid base balance must be eliminated as potentiating factors in patients who require large doses of antiarrhythmic agents to control ventricular arrhythmias.
For more Drug Warnings (Complete) data for QUINIDINE SULFATE (24 total), please visit the HSDB record page.

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Pharmacodynamics
Quinidine is an antimalarial schizonticide, and a class Ia antiarrhythmic agent used to interrupt or prevent reentrant arrhythmias and arrhythmias due to increased automaticity, such as atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia. In most patients, quinidine can lead to an increase in the sinus rate. Quinidine also causes a marked prolongation of the QT interval in a dose-related manner, acts peripherally as an α-adrenergic antagonist, and has anticholinergic and negative inotropic activity. The QT interval prolongation caused by quinidine can lead to increased ventricular automaticity and polymorphic ventricular tachycardias, such as _torsades de pointes_. The risk of _torsades_ is increased by bradycardia, hypokalemia, hypomagnesemia or high serum levels of quinidine. However, this type of rhythm disturbance may appear in the absence of any of them. Patients treated with quinidine may also be at risk of a paradoxical increase in ventricular rate in atrial flutter/fibrillation, and patients with sick sinus syndrome treated with quinidine may develop marked sinus node depression and bradycardia.

C20H24N2O2

324.4168

324.183

C, 74.04; H, 7.46; N, 8.64; O, 9.86

56-54-2

Quinidine hydrochloride monohydrate;6151-40-2;Quinidine sulfate;50-54-4;Quinidine sulfate dihydrate;6591-63-5;Quinidine polygalacturonate;27555-34-6;Quinidine gluconic acid;7054-25-3;Quinidine-d3;1267657-68-0; 747-45-5 (bisulfate); 56-54-2; 1668-99-1 (HCl);

441074

CRYSTALS WITH 2.5 MOL WATER OF CRYSTALLIZATION; CRYSTALS FROM DILUTE ALCOHOL
Occurs as fine, needle-like, white crystals which frequently cohere in masses or as a fine, white powder.

1.2±0.1 g/cm3

495.9±40.0 °C at 760 mmHg

168-172 °C(lit.)

253.7±27.3 °C

0.0±1.3 mmHg at 25°C

1.638

3.44

1

4

4

24

457

4

O([H])[C@@]([H])(C1C([H])=C([H])N=C2C([H])=C([H])C(=C([H])C=12)OC([H])([H])[H])[C@@]1([H])C([H])([H])C2([H])C([H])([H])C([H])([H])N1C([H])([H])[C@]2([H])C([H])=C([H])[H]

LOUPRKONTZGTKE-LHHVKLHASA-N

InChI=1S/C20H24N2O2/c1-3-13-12-22-9-7-14(13)10-19(22)20(23)16-6-8-21-18-5-4-15(24-2)11-17(16)18/h3-6,8,11,13-14,19-20,23H,1,7,9-10,12H2,2H3/t13-,14-,19+,20-/m0/s1

(S)-[(2R,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol

(+)-Quinidine; Conquinine; Pitayine; Chinidin; Conchinin; (8R,9S)-Quinidine;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~154.12 mM)
Ethanol : ~14.29 mg/mL (~44.05 mM)
H2O : ~0.67 mg/mL (~2.07 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.71 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.71 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)